1. Technical Field
The invention relates to an improved process for the preparation of macrocyclic compounds useful as agents for the treatment of hepatitis C viral (HCV) infections.
2. Background Information
The macrocyclic compounds of the following formula (I) are known from the International Patent Application WO 00/59929, U.S. application Ser. No. 09/760,946, filed Jan. 16, 2001, and U.S. Provisional Application No. 60/442,768, filed Jan. 27, 2003, all of which are herein incorporated by reference:
wherein W is CH or N,    R1 is H, halo, C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, C1-6 alkoxy, C3-6 cycloalkoxy, hydroxy, or N(R5)2,    wherein each R5 is independently H, C1-6 alkyl or C3-6 cycloalkyl;    R2 is H, halo, C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, C1-6 thioalkyl, C1-6 alkoxy, C3-6 cycloalkoxy, C2-7 alkoxy-C1-6alkyl, C6 or C10 aryl or Het, wherein Het is a five-, six-, or seven-membered saturated or unsaturated heterocycle containing from one to four heteroatoms selected from nitrogen, oxygen and sulfur;    said cycloalkyl, aryl or Het being substituted with R6,    wherein R6 is H, halo, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, C3-6 cycloalkoxy, NO2, N(R7)2, NH—C(O)—R7; or NH—C(O)—NH—R7, wherein each R7 is independently: H, C1-6 alkyl or C3-6 cycloalkyl;    or R6 is NH—C(O)—OR8 wherein R8 is C1-6 alkyl or C3-6 cycloalkyl;    R3 is hydroxy, NH2, or a group of formula —NH—R9, wherein R9 is C6 or C10 aryl, heteroaryl, —C(O)—R10, —C(O)—NHR10 or —C(O)—OR10,            wherein R10 is C1-6 alkyl or C3-6 cycloalkyl;            D is a 3 to 7-atom saturated alkylene chain;    R4 is H, or from one to three substituents at any carbon atom of said chain D, said substituent independently selected from the group consisting of: C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, hydroxy, halo, amino, oxo, thio, or C1-6 thioalkyl; and    A is an amide of formula —C(O)—NH—R11, wherein R11 is selected from the group consisting of: C1-8 alkyl, C3-6 cycloalkyl, C6 or C10 aryl, C7-16 aralkyl and SO2R11A wherein R11A is C1-8 alkyl, C3-7 cycloalkyl or C1-6 alkyl-C3-7 cycloalkyl;    or A is a carboxylic acid or a pharmaceutically acceptable salt or ester thereof;
The compounds of formula (I) are disclosed as being active agents for the treatment of hepatitis C virus (HCV) infections. The methods disclosed for the preparation of these compounds include many synthetic steps, which involve protection and deprotection of certain reactive groups and leads to an insufficient overall yield. Moreover, the disclosed methods are difficult to implement on a technical scale. The problem underlying the present invention is to provide a process which allows for the manufacture of these compounds on a technical scale with sufficient overall yield.